The 14-3-3 proteins are a conserved family of dimeric phospho-serine binding proteins that interact and modulate the functions of multiple cellular proteins and in so doing regulate many signalling pathways. The 14-3-3 proteins are composed of two 30 kDa monomer units that are each capable of binding a phospho-serine motif via an amphipathic groove. Dimers of 14-3-3 are formed by helix 1 of one monomer interacting with helices 3 and 4 of another monomer. Functionally, 14-3-3 proteins perform multiple roles in regulating cellular protein activities and these functions of 14-3-3 are dependent on its dimeric structure.
14-3-3 proteins are an attractive target for therapeutic purposes. For example, enhanced expression of 14-3-3 proteins has been detected in a variety of disorders, including many human cancers and which correlate with more aggressive tumours and poor prognosis. Because of the biological roles of 14-3-3 proteins, there has been considerable interest in identifying agents that have the ability to modulate 14-3-3 activity, such as small molecules that function as mimics of 14-3-3 phospho-clients. However, while such small molecules have shown activity in vitro, to date they appear to have had limited therapeutic potential.
For a variety of disorders there is a continuing need to identify new possible targets for therapeutic intervention and to identify molecules that have therapeutic potential. The present disclosure relates to use of 14-3-3 proteins as a therapeutic target.